# Elucidating the molecular mechanisms of spinocerebellar ataxia gene TMEM16K in interorganellar communication

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $241,004

## Abstract

Project Summary
 While it is well established that organelles communicate extensively through vesicular transport, recent work
has revealed that essential cellular processes including lipid and calcium homeostasis can be coordinated
through evolutionary conserved membrane contact sites (MCS). MCS are maintained by tethering proteins which
create specialized microdomains that allow the targeted exchange of ions and lipids between the two membranes.
Loss of human orthologs of these proteins have been implicated in a broad range of neurodegenerative diseases.
However, the molecular function of these proteins, as well as the mechanisms underlying how such sites of inter-
organelle contact regulate cellular physiology and pathophysiology remain to be determined. As an ideal entry-
point into this question, we have chosen to study the metazoan ortholog of yeast Ist2, the first established
membrane contacts site tether, which encodes a TMEM16K transmembrane protein. Loss of TMEM16K in
humans is causative for progressive autosomal recessive spinocerebellar ataxia (SCAR10). We have established
that a TMEM16K mouse knockout model recapitulates critical aspects of human disease and have found
TMEM16K absence leads to perturbed dendritic morphology in Drosophila neurons. We have further established
that endoplasmic reticulum (ER) localized TMEM16K directly binds endolysosomal specific
phosphatidylinositols and is required for endolysosomal maturation, suggesting that TMEM16K acts as a critical
mediator of ER-endolysosomal inter-organelle communication. Endolysosomal maturation is required for
proper sorting and degradation of macromolecules, and is emerging as central player in a host of
neurodegenerative diseases. The goal of this proposal is to elucidate the conserved molecular mechanisms
through which TMEM16K mediates endolysosomal maturation at ER-endolysosomal membrane contact sites,
in order to understand their role in neurodegeneration. To accomplish this, we propose to: (1) Identify the
interactome of TMEM16K to reveal molecular pathways perturbed in the disease using novel approach based on
proximity biotinylation and mass spectrometry; and (2) Functionally analyze how TMEM16K pathway facilitates
endolysosomal maturation in health and disease using an in vivo aged Drosophila neuronal model. Overall, by
combining novel technical advancements with comparative biology approaches the implementation of this
proposal will define the molecular mechanism of how ER-localized TMEM16K facilitates endolysosomal
maturation and contributes to the pathophysiology of neurodegeneration. Considering that such communication
at membrane contact sites is emerging as a critical regulatory mechanism for cellular homeostasis, with an
increasing number of components linked to neurodegenerative disease, their better understanding could also
open new avenues for novel therapeutics.
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## Key facts

- **NIH application ID:** 9867610
- **Project number:** 5R21AG061468-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** YUH NUNG JAN
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $241,004
- **Award type:** 5
- **Project period:** 2019-02-15 → 2020-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9867610

## Citation

> US National Institutes of Health, RePORTER application 9867610, Elucidating the molecular mechanisms of spinocerebellar ataxia gene TMEM16K in interorganellar communication (5R21AG061468-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9867610. Licensed CC0.

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